The present invention relates to analogs of dictyostatin, intermediates for the synthesis of such analogs and methods of synthesis of such intermediates and analogs.
References set forth herein may facilitate understanding of the present invention or the background of the present invention. Inclusion of a reference herein, however, is not intended to and does not constitute an admission that the reference is available as prior art with respect to the present invention.
The discovery and development of new chemotherapeutic agents for the treatment of cancer is currently of high importance. Some of the best currently available chemotherapeutic agents are natural products or natural product analogs. For example, Taxol (paclitaxel) is a natural product that is currently being used to treat patients with breast and ovarian cancer among others. A number of analogs of Taxol, including Taxotere (docetaxel), are also powerful anticancer agents.
Recently, the natural product (+)-discodermolide and its analogs have shown great promise as anticancer agents. Discodermolide has been shown to have a mechanism of action similar to Taxol, but it is active against Taxol-resistant cell lines and it is more water soluble than Taxol. Accordingly, it may have a different and/or broader spectrum of action than Taxol and be easier to formulate and administer. Analogs of discodermolide have been made and tested for activity. For example, see Myles, D. C. Emerging microtubule stabilizing agents for cancer chemotherapy, Annual Reports In Medicinal Chem; Academic Press: San Diego, Calif., 2002; pp 125-132. An interesting feature of discodermolide is that both enantiomers are biologically active.

Recently, an unusual macrolactone natural product dictyostatin 1 (sometimes called simply “dictyostatin”) was isolated from two different sponges and a partial structure was assigned as shown below. See Pettit, G. R.; Cichacz, Z. A. Isolation and structure of dictyostatin 1. In U.S. Pat. No. 5,430,053; 1995; Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Boyd, M. R.; Schmidt, J. M. Isolation and structure of the cancer cell growth inhibitor dictyostatin 1. J Chem. Soc., Chem. Commun. 1994, 1111-1112. The configurations at C16 and C19 were not yet assigned in the natural product and the absolute configuration was not known. Dictyostatin shows extremely high potencies against and array of cancer cell lines.

Dictyostatin was also shown to stabilize microtubules, like discodermolide and Taxol. See Wright, A. E.; Cummins, J. L.; Pomponi, S. A.; Longley, R. E.; Isbrucker, R. A. Dictyostatin compounds for stabilization of microtubules. In PCT Int. Appl.; WO62239, 2001. Accordingly, dictyostatin and its analogs show great promise as new anticancer agents. In U.S. patent application Ser. No. 10/655,916, it was shown that novel analogs of dictyostatin are promising anti-cancer agents with potential advantages over Taxol and discodermolide, and taught the syntheses of these analogs.
It remains desirable to further develop analogs of dictyostatin as well at to develop methods of synthesis of dictyostatin analogs and intermediates for use in such methods.